Pulmonary emphysema is a prevalent lung disease defined by permanent enlargement of airspaces, but also associated with systemic effects on organs that include the bone marrow and the cardiovascular system. Little is known about the mechanisms of systemic illness in emphysema and their impact, if any, on the lung disease. The lung destruction, clinically apparent after years of cigarette smoking has been attributed to protease-antiprotease imbalance, chronic inflammation, oxidative stress, and excessive alveolar cell death with loss of pulmonary capillaries that support the alveolar unit. We demonstrated that pluripotent cells contained in adipose stroma, called adipose stem or stromal cells promote capillary growth and limit ischemic tissue damage in models of acute skeletal muscle, myocardial, and cerebral ischemia and these salutary effects are mediated by angiogenic and anti-apoptotic paracrine factors. Given the feasibility of obtaining these stem cells, requiring no or limited ex vivo expansion, we tested the effect of adipose stem cells on cigarette smoke-induced murine emphysema. This form of regenerative treatment resulted in preservation of alveolar surface area and marked protection of the bone marrow from the suppressive effects of smoke on the number and cycling of multiple lineages of progenitor cells. We therefore generated the novel hypothesis that treatment with adipose stem cells will ameliorate the alveolar structural loss induced by cigarette smoking by decreasing lung structural cell death and reducing the loss of bone marrow-derived progenitor cells. To test this novel promising therapy for emphysema and to advance understanding of the crosstalk between the lung and bone marrow in emphysema development, we focused on 3 specific aims: 1. to determine the efficacy of adipose stem cells to limit cigarette smoke-induced murine emphysema; 2. to determine the effect of adipose stem cell treatment on the cigarette smoke-induced bone marrow-derived progenitor cell loss and to establish its importance to the development of emphysema; 3. to establish the role of adipose stem cell-secreted paracrine factors VEGF, HGF, and TSG-6 in the inhibition of lung destruction and of bone marrow hypoplasia induced by adipose stem cell exposure. We have assembled a multidisciplinary team with expertise in emphysema pathobiology, adipose stem cell-, vascular-, and bone marrow stem cell-biology to investigate the proposed comprehensive research plan. If completed, this work will determine the effectiveness, optimal approach, and mechanisms of adult, thus generally ethically accepted, adipose stem cell therapy in a relevant emphysema model, and will accelerate its implementation as a potential therapeutic approach in COPD. PUBLIC HEALTH RELEVANCE: Here we propose a new investigation of the efficacy of and mechanisms underlying the treatment with adipose stromal or stem cells to ameliorate emphysema induced by cigarette smoke in mice. We are uniquely qualified to conduct this study, since we have a combined experience in the research of cigarette smoke-induced lung injury, and basic and translational applications of adult adipose stem cells to other diseases that involve apoptosis of capillary vascular beds. In addition, by studying how adipose stem cells rescue the bone marrow from the deleterious effects of cigarette smoking, this work will study a potentially novel mechanism of cigarette-induced injury, involving the loss of bone marrow-derived progenitor cells. Our work is therefore expected to provide the rationale for a therapeutic strategy that involves the use of ethically acceptable and easily obtainable stem cells in patients with COPD, which may be extended to other diseases in which bone marrow progenitor cell participation is key.